AMD is characterized by the progressive loss of vision in the central visual field attributable to atrophic, exudative and/or hemorrhagic changes in the macula. No pharmacologic treatment has been shown to be effective in preventing, arresting, or reversing loss of vision associated with AMD. The proposed research has focused primarily on drusen, which are accumulations of extracellular material that develop between the retinal pigment epithelium (RPE) and its blood supply, the choriocapillaris. Relatively little is known about the origin or the composition of drusen, even though drusen deposits are considered widely as a significant risk factor for the development of both atrophic and exudative AMD. Preliminary studies of drusen composition have led to the identification of specific drusen-associated molecules (DRAMs), many of which are circulating plasma proteins and known participants in the processes of fibrinolysis, thrombosis, inflammation, and/or the immune response. In this proposal, the emphasis is on drusen biogenesis, the identification of the ligands for DRAMs in the RPE-choroid in the transcellular pathways involved in DRAM deposition. The experimental cell line in this as well as the two companion proposals are designed to clarify the relationship between ocular drusen, related choroidal abnormalities, and the subsequent development of atrophic AMD. In so doing, the applicants hope to establish a conceptual framework for pursuing additional basic and clinical research into the causes and prevention of AMD.